Age-Dependent Levels of Protein Kinase Cs in Brain: Reduction of Endogenous Mechanisms of Neuroprotection

Abstract

Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.

Anticonvulsive and Neuroprotective Effects of Eupafolin in Rats Are Associated with the Inhibition of Glutamate Overexcitation and Upregulation of the Wnt/β-Catenin Signaling Pathway

“…The inhibition of PKC or Akt that accompanies neuronal death has been observed in the brain under excitotoxic conditions, and this excitotoxic brain damage also appears to be prevented by PKC or Akt activation. 47,48 In addition, PKC has been found to phosphorylate the C-terminal intracellular regulatory domain of the AMPA receptor subunit, including GluR2, 49 and this PKC-GluR2 axis is known to play a neuroprotective role in glutamate-induced neurotoxicity. 50 In our study, we found that the KA-induced decreases in the phosphorylation of the AMPA receptor subunit GluR2 and PKCα were significantly increased by eupafolin, implying that the PKC-GluR2 axis is also involved in the anticonvulsant and neuroprotective effects of eupafolin.…”

Chronic Intermittent Ethanol Exposure Alters Behavioral Flexibility in Aged Rats Compared to Adult Rats and Modifies Protein and Protein Pathways Related to Alzheimer’s Disease

“…Given that Prkcd is expressed in the hippocampus and dentate gyrus and can regulate ethanol’s effect on extrasynaptic GABA A receptors, CIEE might have upregulated Prkcd expression in the hippocampus of the aged rats, thereby altering extrasynaptic tonic GABAergic currents and in turn contributing to the impaired behavioral flexibility. Moreover, Prkcd had been implicated in AD . Increased PRKCD levels were found in brain tissues of patients with AD compared to those of individuals without the disease, and the inhibition of PRKCD expression was shown to reduce BACE1 expression and amyloid-β levels .…”

Utilizing an Animal Model to Identify Brain Neurodegeneration-Related Biomarkers in Aging

“…Neurodegenerative diseases are one of the leading causes of death and disability worldwide. PAK1 is involved in intracellular signaling pathways downstream of in-tegrins and receptor-type kinases and plays an important role in cytoskeleton dynam-ics, cell adhesion, migration, proliferation, apoptosis, mitosis, and vesicle-mediated transport processes as well as involving in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s Disease (AD) and cerebral ischemia [ 61 ]. PAK1 expres-sion was altered with aging.…”